Abstract 3585: Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo

Abstract

Purpose: MAPK-pathway is one of the most important pathways for a new anticancer drug development. We performed a high-throughput screening for compounds that induce expressions of p15INK4b, and finally identified a novel MEK1/2 inhibitor JTP-74057 (GSK1120212) being evaluated in clinical trials. We characterized its antitumor activities in vitro and in vivo. Experimental design: The MEK inhibitory activity was evaluated using recombinant proteins, and its specificity was confirmed against multiple kinases. Several colorectal cancer cell lines were used for proliferation assay, apoptosis assay, and xenograft model. Results: JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit other 98 kinase activities. Treatment with JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most colorectal cancer cell lines, which we tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth both of HT-29 and COLO205 xenografts in nude mice. Interestingly, the tumor regression was observed only in COLO205 xenografts, and COLO205 was also much more sensitive to JTP-74057 for inducing apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. Conclusions: JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis might be an important factor for the estimation of in vivo efficacy, and the treatment with an Akt inhibitor enhanced the induction of apoptosis. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2011-3585

B-Raf Inhibitors Induce Epithelial Differentiation in BRAF-Mutant Colorectal Cancer Cells

“…Doxycycline administration to HT29/V600E shRNA carrying mice reduced the number of cells expressing the proliferation marker Ki-67. In agreement with earlier studies (16,17), tumor regression was also observed in mice treated with vemurafenib or trametinib (Fig. 7C).…”

“…Nevertheless, these inhibitors still elicited partial responses and stabilized disease in some patients (14,15). Depending on their mutational landscape, BRAF-mutant colorectal carcinoma cell lines display differential sensitivity toward B-Raf or MEK inhibitors in tissue culture and xenograft models (4,13,(16)(17)(18). Thus, these compounds still hold clinical promise, in particular if their combination with other substances is considered and once the complex pathology and genetic heterogeneity of colorectal carcinoma are better understood.…”

Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

“…Kidney-Our laboratory and others have previously reported that a 1 mg/kg dose of trametinib inhibits ERK1/2 phosphory- lation in mice (16,27). We verified that trametinib (1 mg/kg, i.p.)…”

“…Trametinib has been well characterized as a potent and specific inhibitor of MEK1/2 with an IC 50 of 0.92-3.4 nM in various cell lines and shows limited inhibitory activity against at least 98 other kinases (15,16). RPTC were treated with 0.3, 1, or 10 nM trametinib, and at 10 nM trametinib, ERK1/2 phosphorylation was completely inhibited after 4 h (Fig.…”

MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

“…To evaluate the effects of GSK1120212, a suspension of 1  10 7 cells (in 50 mL of PBS) with 50 mL of Matrigel (Okajima cell line) or 5  10 6 cells (in 50 mL of PBS) with 50 mL of Matrigel (SNU-16 cell line) was subcutaneously inoculated into the right flank of each NOD/SCID mouse (n ¼ 5); treatment was then initiated when the tumors in each group achieved an average volume of approximately 150 mm 3 . In the treatment groups, GSK1120212 (0.5 or 1.0 mg/kg) was administered by oral gavage daily for 7 days based on the results of a previous study (20); the control animals received 0.5% methylcellulose as a vehicle. The tumor volume was calculated as the length  width 2  0.5.…”